Chetomin

Chetomin, an antibiotic metabolite of chaetomium cochliodes, is an inhibitor of HIF-1 by weaken transcription of HIF-1 and recently is raised interests as a cancer chemotherapeutic agent.[1]
HIF-1 (hypoxia-inducible factors 1) is transcription factor which respond to changes of cellular environment oxygen. [2] HIF-1 complex belongs to the PAS subfamily of the basic helix-loop-helix family of transcription factors and is composed of an alpha subunit and a beta subunit which formed a heterodimer. [3] HIF-1 can upregulate several genes such as glycolysis enzymes, vascular endothelial growth factor to promote survival rate of cells in hopoxia conditions through binding to HIF-responsive elements in the promoters. NF- Kappa B was shown a direct modulator of HIF-1alpha in normal condition but in low-oxygen conditions HIF-1alpha still stable with an unknown mechanism. [4]
Chetomin selectively inhibited HIF-1 activities through disruption of the interaction of HIF-1with its transcriptional coactivator p300. Early-passage human fibrosarcoma HT1080 cells stably transfected EGFP plasmid with a hypoxia-responsive 5HRE-hCMVmp promoter were pretreated with chetomin showed dose and incubation-time dependent EGFP fluorescence signal suppression. And pretreatment of 150nM chetomin for 4h showed maximum suppressive effects, indicated the inhibition of HIF-dependent transcription. Also, 150nM chetomin decreased expression of VEGF and CA9 under hapoxic conditions in HT1010 cells. Chetomin increased cell survival rate under hypoxia compared mormoxia conditions, indicated that chetomin can enhanced radiation treatment efficacy under severely hypoxic conditions.[5]
References:
[1] Timothy R. Welch and Robert M. Williams. Studies on the Biosynthesis of Chetomin: Enantiospecific Synthesis of a Putative, Late-Stage Biosynthetic Intermediate. Tetrahedron (2013) 69(2): 770–773
[2] Smith TG, Robbins PA, Ratcliffe PJ. The human side of hypoxia-inducible factor. Br. J. Haematol. (2008)141(3): 325–34
[3] Jiang BH, Rue E, Wang GL, Roe R, Semenza GL. Dimerization, DNA binding, and transactivation properties of hypoxia-inducible factor 1. J. Biol. Chem. (1996) 271(30):17771-17778
[4] Van Uden P, Kenneth NS, Rocha S. Regulation of hypoxia-inducible factor-1 alpha by NF-kappa B. Biochem. J. (2008) 412(3): 477-484
[5] Adrian Staab, Jürgen Loeffler, Harun M Said, Désirée Diehlmann, Astrid Katzer, Melanie Beyer, Markus Fleischer, Franz Schwab, Kurt Baier, Hermann Einsele, Michael Flentje and Dirk Vordermark. Effects of HIF-1 inhibition by chetomin on hypoxia-related transcription and radiosensitivity in HT 1080 human fibrosarcoma  Cells. BMC Cancer (2007) 7 :213

Chetomin, targeting HIF-1alpha/p300 complex, exhibits antitumour activity in multiple myeloma.[Pubmed:26867162]

Br J Cancer. 2016 Mar 1;114(5):519-23.

BACKGROUND: Multiple myeloma (MM) is an incurable clonal plasma cell malignancy. The constitutive expression of HIF-1alpha in MM suggests that inhibition of HIF-1alpha-mediated transcription represents an interesting target in MM. METHODS: As p300 is a crucial co-activator of hypoxia-inducible transcription, disrupting the complex HIF-1alpha/p300 to target HIF activity appears to be an attractive strategy. RESULTS: We reported that Chetomin, an inhibitor of HIF-1alpha/p300 interaction, exhibits antitumour activity in human myeloma cell lines and primary MM cells from patients. CONCLUSIONS: Our data suggest that Chetomin may be of clinical value in MM and especially for patients characterised by a high EP300/HIF-1alpha expression and a poor prognosis.

Chetomin induces degradation of XIAP and enhances TRAIL sensitivity in urogenital cancer cells.[Pubmed:21165560]

Int J Oncol. 2011 Feb;38(2):365-74.

Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) is one of the most promising anti-cancer agents, but some tumor types develop resistance to TRAIL. Here, we report that Chetomin, an inhibitor of hypoxia-inducible factors, is a potent enhancer of TRAIL-induced apoptosis. TRAIL or Chetomin alone weakly induced apoptosis, but the combination of Chetomin and TRAIL synergistically induced apoptosis in prostate cancer PC-3 cells. The combination of Chetomin and TRAIL induces the activation of caspase-3, -8, -9 and -10. Among the apoptotic factors related to the TRAIL pathway, Chetomin markedly decreased the X-linked inhibitor of apoptosis (XIAP) protein levels in a dose-dependent manner, but other IAP family members, TRAIL receptors and Bcl-2 family members were not altered by Chetomin. Using XIAP siRNA instead of Chetomin, down-regulation of XIAP sensitized PC-3 cells to TRAIL-induced apoptosis. Conversely, transient transfection of XIAP reduced the apoptotic response to combined treatment with Chetomin and TRAIL. Treatment with Chetomin induced a rapid decrease in XIAP protein levels but had no effect on XIAP mRNA levels. Since Chetomin-mediated XIAP down-regulation was completely prevented by proteasome inhibitors, it was suggested that Chetomin induces the degradation of the XIAP protein in a proteasome-dependent manner. Additionally, Chetomin also sensitized renal cancer Caki-1 cells and bladder cancer UM-UC-3 cells to TRAIL-induced apoptosis via down-regulation of XIAP. Co-treatment of Chetomin and TRAIL did not enhance apoptosis in normal peripheral blood mononuclear cells (PBMC). Taken together, these findings suggest that TRAIL and Chetomin synergistically induce apoptosis in human urogenital cancer cells through a mechanism that involves XIAP down-regulation by Chetomin.

Studies on the Biosynthesis of Chetomin: Enantiospecific Synthesis of a Putative, Late-Stage Biosynthetic Intermediate.[Pubmed:24489414]

Tetrahedron. 2013 Jan 1;69(2):770-773.

The enantiospecific synthesis of desthioChetomin, a putative biosynthetic intermediate of the epidithiodioxopiperazine natural product Chetomin, is described. A diastereoselective N-alkylation was employed to form the key C3-N1' bond of the heterodimeric indoline core, followed by peptide coupling and dioxopiperazine cyclization with the requisite N-methyl amino acids. A related sarcosine-derived dioxopiperazine was prepared in the same manner. The first proposed biosynthesis of Chetomin is also detailed in the text.

Enhanced antitumor activity and mechanism of biodegradable polymeric micelles-encapsulated chetomin in both transgenic zebrafish and mouse models.[Pubmed:25175172]

Nanoscale. 2014 Oct 21;6(20):11940-52.

Chetomin is a promising molecule with anti-tumor activities in the epipolythiodioxopiperazine family of fungal secondary metabolites; however, strong hydrophobicity has limited its further applications. In this work, Chetomin was encapsulated into polymeric micelles to obtain an aqueous formulation, and the Chetomin loaded micelles (Che-M) exhibited small particle size and high encapsulation efficiency. When the concentration of copolymer was higher than the critical gelation concentration, the Che-M could form a thermosensitive hydrogel (Che-H), which was free-flowing sol at ambient temperature and converted into a non-flowing gel at body temperature. The molecular modeling study has indicated that Chetomin interacted with PCL as a core, which was embraced by PEG as a shell. Che-M showed equal cytotoxicity with free Chetomin, but the apoptosis inducing effects of Che-M were more significant. Besides, Che-M could increase the GSSG level, decrease the GSH level, and increase the ROS in CT26 cells. Furthermore, stronger inhibitory effects of Che-M were observed on embryonic angiogenesis, tumor-induced angiogenesis and tumor growth in transgenic zebrafish models. In addition, Che-M was effective in inhibiting tumor growth and prolonging survival in a subcutaneous CT26 tumor model. In a colorectal peritoneal carcinomatosis model, both Che-M and Che-H showed excellent therapeutic effects, but Che-H was more effective. In conclusion, Che-M and Che-H may serve as candidates for cancer therapy.